Biopharmaceutical as well as clinical production facilities increasingly employ single-use containers including pre-sterilized, single-use, plastic tubing and collapsible plastic bags for solution storage and bioreactor applications. In addition, the downstream processing and purification of bioreactor solutions is increasingly achieved with single-use, unit-operational platforms designed for the aseptic purification of solutions by normal flow filtration (NFF), tangential flow filtration (TFF), chromatography and bioreactor applications.
Single-use platforms for downstream biopharmaceutical purification typically consist of an integrated assembly of filter elements or columns, flexible tubing, plastic connectors and solution storage bags, segments of peristaltic pump tubing as well as integrated sensors. Such assemblies are designed and pre-assembled for a specific purification process. Special, integral plastic connectors provide aseptic hook-up to external, single-use bioreactors and/or buffer solutions. In the final configuration, all elements of the purification platform are assembled, pre-sterilized by gamma-irradiation. Dedicated peristaltic pumps are used to aseptically propel the process solution and buffers through the purification tube manifold.
Pre-sterilized, single-use bag manifolds such as those used in bio-pharmaceutical production (see for example U.S. Pat. No. 6,712,963) lack the ability to monitor and validate important, analytical solution parameters during the processing of biopharmaceutical solutions. The use of such bag manifolds, for example, in preparative chromatography or tangential flow filtration (TFF) or fluid transfer generally, is severely limited by the general lack of pre-sterilized, pre-calibrated, pre-validated in-line sensors and detectors.
In-line, flow through-type sensors and detectors are well known in industry and are extensively used in analytical laboratories, pilot plants and production facilities. Prior art in-line sensors and detectors are difficult to sterilize, require in-field calibration and validation by an experienced operator before use, and are very expensive, often costing thousands of dollars. Consequently, prior art sensors and detectors are not suited for a single-use sensor application.
The need for pre-calibrated sensors arises from the fact that sensor calibration after sterilization of the sensor-manifold assembly is not possible without danger of re-contamination. On the other hand, sensor insertion into a pre-sterilized manifold just prior to use is also problematic since it would require the maintenance of a carefully controlled aseptic environment during on-site sensor calibration, sterilization and sensor insertion process. Breakdown of aseptic conditions could result in serious process contamination and give rise to unacceptable economic losses.
In-line sensors for use in bioprocessing applications must be designed to satisfy several additional requirements. For example, they must meet government regulations regarding device traceability and validation. In addition, in-line sensors must meet the application requirements for accuracy and precision. These requirements present extra challenges and pose unique problems when the in-line sensor is to be disposable and suitable for single use as desired. Furthermore, single-use sensors must meet economic requirements, i.e. sensors must be low cost, easy to replace with negligible disposal expense.
Meeting sensor sterilization requirements represents another very significant sensor design challenge. This is especially the case, when the sensor is intended for single-use bag manifold applications such as those described in the U.S. Pat. Nos. 6,712,963, 7,052,603 and 7,410,587 and U.S. Patent Application Publication No. 2006/0118472 (all of which are incorporated herein by reference).
In order to maintain a high quality of purification to a given set of specifications, pre-calibrated, single-use in-situ sensors are used for monitoring temperature, pressure, conductivity, and other solution parameters. Such in-line (in-situ) sensors must be designed to withstand the conditions of gamma-irradiation (˜35 kGy) and/or steam (˜123° C.) sterilization. The sensor may also endure sanitizing by ethylene oxide gas, electron-beam irradiation or a sodium hydroxide solution.
For many single-use sensor applications, e.g. for bag manifolds, the preferred sterilization method by the industry is by gamma or electron-beam irradiation. The main advantage of gamma and electron-beam irradiation lies in that the entire, pre-assembled manifold, including bags, tubing, connectors and sensors, can be first sealed in a shipping bag and then exposed to sterilizing radiation or electron-beam bombardment. The entire manifold assembly within the shipping bag remains sterile for a rated period, unless the shipping bag is comprised during shipment or storage.
For device/performance traceability, pre-calibrated sensors must contain electronically accessible sensor ID, sensor-specific calibration data and lot-specific sensor performance data. This can be accomplished with integration of a non-volatile, gamma-stable memory device into each sensor. Sensor specific calibration information and ID number are stored in the memory device after successful factory calibration of the sensor. In addition, the calibration date stamp as well as lot-specific sensor performance data is useful information stored in the non-volatile memory. In addition, the device must have sufficient memory capacity to store relevant sensor data during processing for post-production review and analysis. See U.S. Pat. No. 7,857,506 and U.S. Pat. No. 7,788,047 (which are incorporated herein by reference).